1 alpha , 2 alpha ; 6 beta , 7 beta -DIMETHYLENE STERIODS

ABSTRACT

1 Alpha ,2 Alpha ;6 Beta ,7 Beta -Dimethylene-17 Alpha -oxyprogesterones of the formula   WHEREIN R is H or an acyl radical, have progestational activity without ovulation inhibiting activity.

United States Patent 1 Hofmeister et al.

:11 3,714,207 1 Jam-30, 1973 41 la, 20:; 6B, 7/3-DIMETHYLENE STERIODS [75] lnventors: Helmut llofmeister; Hermann Steinbeck; Rudoll Wiechert, all of Berlin,

[21] App]. No.: 33,961

[30] Foreign Application Priority Data May 2, 1969 Germany ..-.....P i9 23 378.4

[52] U.S. Cl.....260/397.4, 260/239.5, 260/239.55 R,

[51] Int. Cl ..C07c 169/34 [58] Field of Search ../Machine Searched Steroids [56] References Cited UNITED STATES PATENTS 3,365,446 l/l968 Cross et al ..260/239.55

Cross et all ..260/397.4 Laurent et al. ..260/397.4

Primary ExaminerHenry A. French Attorney-Millen, Raptes & White 57] ABSTRACT la ,2a;6B,7B-Dimethylene-l7a-oxy-progesterones of the formula Yjo-R wherein R is H or an acyl radical, have progestational activity without ovulation inhibiting activity.

6 Claims, No Drawings la, 20:; 6B, 7B-DIMETHYLENE STERIODS BACKGROUND OF THE INVENTION This invention relates to novel la,2a;6B,7B- dimethylene steroids, to a process for their production and their use as progestational agents.

SUMMARY OF THE INVENTION DETAILED DISCUSSION 1a,2a;6B,7B-Dimethylene-l7a-hydroxyprogesterone and its l7-esters can be represented by the formula wherein R is a hydrogen atom or, an acid residue.

Suitable acid residues R are preferably those of physiologically acceptable acids. Preferred acids are organic carboxylic acids containing up to carbon atoms, most preferably fatty acids of l to 8 carbon atoms. The acids can be saturated or unsaturated, straight chain or branched, mono-, dior polybasic, or substituted, e.g., with one or more hydroxy, 0x0 or amino groups, and/or halogen atoms. Also suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic, or heterocyclic acids which can likewise be substituted in a suitable manner.

Specific examples of compounds of this invention wherein R is the acyl radical of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecylic acid, trimethylacetic acid, diethylacetic acid, tert.-butylacetic acid, phenylacetic acid, cyclopentylpropionic acid, oleic acid, lactic acid, mono-, di-, and trichloroacetic acid, aminoacetic acid, diethylamino-, piperidino-, and morpholinoacetic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, etc. Also suitable are those wherein R is the acid residue of an inorganic acid, such as, for example, sulfuric and phosphoric acid.

Although the esterified compounds of this invention are preferably those of Formulal in which the l7a-oxy group is an ester of an acyloxy acid, e.g., lower-alkanoyloxy, also included are those which are esters of acyloxy acids of, for example, an aryl or alkaryl acid, e.g., benzoic, 2,3 or 4methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diemthylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, anaphthoic, 3-methyl-a-naphthoic, an aromatic hydroxyacid, e.g., salicylic acid, an aromatic aminoacid, e.g., para-aminosalicylic, para-aminobenzoic, other aromatic hetero-substituted acids, e.g., 2,3,4-trimethoxybenzoic, carbamic acids, e.g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allophanic, or a heterocyclic acid, e.g., B-

furyl-carboxylic, N-methylpyrrolidyl-Z-carboxylic, apicolinic, indole-2-carboxylic, 6-hydroxy-indolyl-3- acetic, N-methylmorpholyl-Z-carboxylic lysergic, pyrrolyl-Z-carboxylic, or other acyl acid.

As stated above, also included as compounds of this inventionare those wherein R is an esterified hydroxy group in which the ester is an ester of an inorganic acid, e.g., sulfuric and phosphoric acid, both in free acid form and as salts of alkali and alkaline earth metals,

e.g., Na and Ca.

Although the process of this invention is directed to the production of the compounds of Formula I, it will be apparent the process can be used for the production of 1a,2a,6[3,7B-dimethylene-A-3-ket0 steroids generally, from the corresponding 4-chlor0 compounds, e.g., those having a fl-hydroxy, -keto, B-acetyl,

B-hydroxyacetyl, fl-hydroxyacetyl-a-hydroxy, a-ethynyl-l7B-hydroxy-a-methyl-[Hi-hydroxy, etc., group at the l7-positi0n.

The invention relates further to a process for the preparation of compounds of Formula I wherein 4- chloro-st'eroid of the formula CH: (II) wherein R has the values given above, is treated with hydriodic or hydrobromic acid, preferably in the presence of a lower-aliphatic carboxylic acid. Surprisingly, the hydrohalic acid causes the chlorine atom to be eliminated from the 4-position of compounds of general Formula II to produce the corresponding 4- deschloro-7B-halomethyland 4-deschloro-la,7B- bishalomethyl-compounds. I To reform the cyclopropane rings in the 6,7-, or 1,2- and 6,7-position, the 4-deschloro-7B-halomethyl and 4-deschloro-la,7flbishalomethyl compounds, which have, the following formula:

respectively,

The hydrohalic acid can be caused to react with the starting steroid (II) by adding the acid to the dissolved steroid and heating the reaction solution, .preferably at the boiling point of the reaction mixture. Suitable solvents are those which are inert with respect to both the steroid and the hydrohalic acid. Inert solvents are, for example, ethers, e.g., tetrahydrofuran and dioxane, hydrocarbons, e.g., hexane and benzene, chlorinated hydrocarbons, e.g., methylene chloride and chloroform, and, in particular, lower aliphatic carboxylic acids, e.g., formic acid and acetic acid. In a preferred embodiment, the hydrohalic acid HX is liberated during the reaction from an alkali salt thereof with a lower-carboxylic acid, which also serves as the reaction solvent.

In order to obtain a complete elimination of the chlorine atom in the 4-position, the solution must be heated above room temperature, e.g., under reflux conditions, for several hours. Under these conditions, a further reaction simultaneously occurs, viz., the 63,713- methylene group is split, with the formation of the 7B- halomethyl compound (Illa). The Ia,2a-methylene group is likewise at least partially cleaved to also produce the corresponding 1a,7B-bishalomethyl compound (lllb).

In order to form the methylene group in the 6,7-position and in the 6,7- and 1.,2-positions, respectively, the reaction products (Illa, IIIb) are subsequently treated with a base strong enough to dehydrohalogenate these halomethylene compounds. Suitable bases are inorganic bases, e.g., sodium, hydroxide, potassium hydroxide, potassium carbonate, calcium oxide and aluminum oxide, as well as organic bases known to act as dehydrohalogenating agents, e.g., a heterocylic aromatic amine, collidine, lutidine, pyridine, etc.

When a strong base, e.g., sodium or potassium hydroxide, is employed, the splitting off of hydrogen halide can advantageously be conducted in an alcoholic solution, e.g., at room temperature or with heating. When the compound being dehydrohalogenated is esterified in the l7-position, a simultaneous saponification of the l7-ester can occur. The desired ring closure to the la,2a;6fl,7B-dimethylene can also be conducted by agitating the 7-halomethyl' (Illa) or l,7- bishalomethyl compound (Illb), dissolved in an organic solvent, for several hours with a weak base, e.g., aluminum oxide. Under these conditions, a l7-ester group is not attacked.

The subsequent esterification of the l7a-hydroxy group of the reaction product (I, R=H) can be conducted under conditions conventionally employed for the esterification of lIla-hydroxy-progesterone, e.g., by reaction with a reactive acid derivative of the selected acid in the presence of a basic esterification agent. Examples of such reactive acid derivatives are acid anhydrides or halogenides. Examples of basic agents are pyridine, collidine, lutidine, etc. The esterification is preferably conducted with heating.

In order to produce water-soluble esters, the 17- hydroxy product is esterified to an acid addition salt of a l7a-aminoacylate ester thereof, e.g., dimethylamino, diethylamino-, piperidino-, and morpholine-acetates, and into alkali-metal 1 salts of dicarboxylic acid monoesters, e.g., succinate, sulfuric acid esters, and phosphoric acid esters thereof. The method of preparation of such soluble esters is well known in the art.

4 la,2a;6B,7B-Dimethylene-N-Ci-ketosteroids unsubstituted in the 4-position have not been described heretofore. They cannot be obtained from the corresponding A""-3-ketosteroids, because methylating agents react only with the A -double bond of such compounds to produce l,2-methylene-A"-3-ketosteroids.

The novel dimethylene steroids of Formula I possess gestagenic activity comparable to that of the corresponding 4-chloro compounds. However, in contrast to the corresponding 4-chloro compounds, they do not effect an inhibition of ovulation, even at high dosages. Because of this marked dissociation of gestagenic and ovulation-inhibiting activities, the compounds of this invention (I) can be advantageously employed for the treatment of gynecologic disturbances where contraception is not desired, e.g., primary amenorrhea and secondary amenorrhea of long duration, cycle disturbances due to insufficient corpus leteum function, endometriosis, hypoplasia of the uterus, premenstrual discomforts, mastopathia, etc. The dosage is determined in part by the seriousness of the disease. In general, the daily dose is between 1 and mg.

The compounds of Formula I possess progestational activity. For use as progestational agents, they can be formulated into conventional drug forms with the additives, carrier substances, and flavoring agents customary in pharmaceutical preparations which do not deleteriously react with the effective agents, employing conventionalmethods. For oral application, particularly suitable are tablets, dragees, capsules, pills,

suspensions and solutions. Such compositions can employ, for example, water, alcohol, polyethylene glycols, gelatin, sucrose, lactose, amylose in solutions and suspensions and magnesium stearate, talc, starch, sugars, etc., in tablets.

Particularly preferred are pharmaceutical preparations containing a compound of this invention adapted for oral administration, especially those conventionally employed in the treatment of gynecological disturbances.

The concentration of the compound of this invention (I) in the thus-formulated drugs is also dependent on the form of application. Solid formulations for oral administration, e.g., tablets and dragees, preferably contain 0.1 to 10 mg. of effective agent per unit. Solutions for parenteral application preferably contain 1 to 20 mg. per 1 ml. ofsolution.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1 10 g. of 4-chloro-l7-acetoxy-la,2a;6fl,7fidimethylene-4-pregnene-3,20-dione is heated under reflux with 35 g. of potassium iodide in 100 ml. of concentrated formic acid for 18 hours with the introduction of'nitrogen. The solution is then stirred into acetic acid-ice water. The precipitate is vacuum-filtered, taken up'in methylene chloride, and the solution is washed successively with dilute sodium thiosulfate solution and water. The crude product is chromatographed'on silica gel, thus obtaining with 2.5 3 percent of acetone-methylene chloride, 1.0 g. of l7-acetoxyla,7B-bisiodomethyl-4-pregnene-3,20-dione, m.p. 194-1 95 C. (with decomposition). UV: e 15,600.

With 6-8 percent of acetone-methylene chloride, 2.7 g. of 17-acetoxy-7B-iodomethyl-la,2a-methylene-4- pregnene-3,20-dione is eluted, m.p. 225227 C. (under decomposition). UV: 16,100.

a. 700 mg. of l7-acetoxy-7/3-iodomethyl-101,201- methylene-4-pregnene-3,20-dione is stirred in 25 ml. of benzene with 12 g. of basic aluminum oxide for 12 hours. Then, the solution is decanted, and the aluminum oxide is washed out several times with acetone. After the solvent has been distilled off, 330 mg. of 17- acetoxy-la,2a;6B,7/3-dimethylene-4-pregnene-3,20- dione is obtained, m.p. 263.5 265.5 C. (acetonehexane). UV: e 15,500.

b. 850 mg. of l7-acetoxy-la,7B-bis-iodomethyl-4- pregnene-3,20-dione is stirred in 30 ml. of benzene with 12 g. of basic aluminum oxide, and worked up as set forth above. After recrystallization from acetonehexane, 250 mg. of l7-acetoxy-la,2a;6B,7B- dimethylene-4-pregnene-3,20-dione is obtained, m.p. 261-263C.

The two prepurified iodomethyl compounds (a) and (b) can also be reacted in the form of a mixture with benzene in basic aluminum oxide to obtain l7-acetoxyla,2a;6/3,7B-dimethylene-4-pregnene-3,20-dione.

EXAMPLE 2 17 g. of 4-chloro-l 7-acetoxy- 1 a,2a;6B,7B- dimethylene-4-pregnene-3,20-dione is heated under reflux in 325 ml. of concentrated formic acid with 65 g. of potassium iodide for 3 days, with the introduction of nitrogen. Then, the dark-colored solution is stirred into acetic ice water, the precipitate is vacuum-filtered, and taken up in methylene chloride. The solution is successively washed with dilute sodium thiosulfate solution and water. The thus-obtained crude product, 17- acetoxy-7B-iodo-methyl-la,2a-methylene-4-pregnene- 3,20-dione is stirred, for purposes of cyclization and saponification, in a mixture of 190 ml. of methylene chloride and 650 ml. of methanol with 290 ml. of 1N NaOl-l solution for 17 hours at room temperature. Thereafter, the solution is substantially concentrated under a vacuum, and the product is precipitated in ice water. The precipitate is vacuum-filtered, dried, and chromatographed on silica gel with 33-39 percent acetone/pentane, thus obtaining 2 g. of l7-hydroxy- 101,20:;6bs,7B-dimethylene-4-pregnene-3,20-dione, m.p.

250252 C. (acetone/hexane). UV: e 15,400.

EXAMPLE 3 1.7 g. of 17-hydroxy-la,2a;6B,7B-dimethylene-4- pregnene-3,20-dione is heated under reflux in 20 ml. of pyridine with 10 ml. of acetic acid anhydride for 5 days with the introduction of nitrogen. The solution is then stirred into sulfuric acid-ice water, the precipitate is vacuum-filtered and washed several times with water. After conducting a chromatography on silica gelwith l3-20 percent acetone/pentane and recrystallization, 400 mg. of l7-acetoxy-la,2a;6B,7B-dimethylene-4- pregnene-3,20-dione is obtained, m.p. 264-265 C.

EXAMPLE 4 500 mg. of l7-hydroxy-la,2a;6B,7B-dimethylene-4- pregnene-3,20-dione is heated under reflux with 1 ml. of propionic acid anhydride in 2 m1. of pyridine for 3 days. Then the solution is poured into sulfuric acid-ice water, and the reaction product is extracted with methylene chloride. After chromatography on silica gel with 21-25 percent acetone/pentane and recrystallization, 170 mg. of 17-propionyloxy-la,2a;6fl,7B- dimethylene-4-pregnene-3,20-dione is obtained, m.p. 220-223 C. (acetone/hexane). UV: 6 15,500.

EXAMPLE 5 800 mg. of l7-hydroxy -la,2a;6B,7B-dimethylene-4- pregnene-3,20-dione is heated under reflux, as described in Example 1, with 3 ml. of butyric acid anhydride in 8 ml. of pyridine for 5 days. After steam distillation, extraction of the product with methylene chloride, and chromatography on silica gel with 20-27 percent acetone/pentane, 800 mg. of l7-butyryloxyl01,20:;6B,7fl-dimethylene-4-pregnene-3,20-dione is obtained in the form ofa foam. UV: e 14,000.

EXAMPLE 6 500 mg. of l7-hydroxy-la,2a;6B,7B-dimethylene-4 pregnene-3,20-dione is heated under reflux with 2 ml. of caproic acid anhydride in 4 ml. of pyridine for 3 days. After working up by means of ice water precipitation, extraction with methylene chloride, and chromatography on silica gel with 18-21 percent acetone/hexane, mg. of l7-hexanoyloxy-la,2 0:;63,7Bb-dimethylene-4-pregnene-3,20-dione is obtained in the form of an oil. UV: e 15,100.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

1. A process for the production of a compound which comprises the steps of a. reacting 4-chlorowith hydriodic or hydrobromic acid; and

b. reacting the thus-produced 4-deschloro product with a dehydrohalogenating base.

2. A process according to claim 1 wherein the starting 4-chloro steroid is the l7-acetate.

3. A process according to claim 1 wherein the dehydrohalogenating base is aluminum oxide.

4. A process according to claim 1 wherein the starting 4-chloro steroid is reacted with hydrogen iodide.

5. A process according to claim 1 wherein step (a) is conducted in the presence of a lower-aliphatic acid.

6. A process according to claim 5 wherein the loweraliphatic acid is formic acid.

(acetone/hexane .UiHTED STATES PATENT OFFICEv CERTIFICATE OF CORRECTION Patent No. 3 ,714 207 Dated n ry 30 1973 lnventofls) Helmut Hofmelstemet a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

COLUMN 5, LINE 48, EXAMPLE 2: "la,2a;6 s" should read COLUMN 6, LINE 31, EXAMPLE 6: "6;,78b" should read COLUMN 6, CLAIM 1 LINE 44: "A process for the production of a compound should read. A process for the production of;1oz,2a,6B,7(3dimethylenel7 othydroxy progesterone end l7-esters thereof Signed and sealed this 27th day of November 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. RENE D. TEGTMEYER Attesting Officer I Acting Commissioner of Patents FORM PO-1050 (10 usco -pc suave-P69 t *1 us. covzmmzm PRINTING orrg c 19 59 0-366-334, 

1. A process for the production of a compound which comprises the steps of a. reacting 4-chloro- with hydriodic or hydrobromic acid; and b. reacting the thus-produced 4-deschloro product with a dehydrohalogenating base.
 2. A process according to claim 1 wherein the starting 4-chloro steroid is the 17-acetate.
 3. A process according to claim 1 wherein the dehydrohalogenating base is aluminum oxide.
 4. A process according to claim 1 wherein the starting 4-chloro steroid is reacted with hydrogen iodide.
 5. A process according to claim 1 wherein step (a) is conducted in the presence of a lower-aliphatic acid. 